This invention relates to 3-quinuclidinyl butanoates and propanoates and which are lung-selective antimuscarinic bronchodilators. Thus these compounds are particularly useful in the treatment of chronic obstructive airways disease (COAD) and asthma.
COAD is a term encompassing conditions which exhibit, to differing extents, several major progressively developing clinicopathological features, namely inflammatory swelling of airway walls, hypertrophy of submucosal glands, and hyperplasia of epithelial secretory cells leading to hypersecretion of viscous mucous which cannot be cleared effectively, progressive increase in irreversible bronchospasm and decrease in lung elastic recoil. This complex pathway results in progressive loss of lung function, with respiratory impairment, increasing morbidity and, finally, death.
Thus, COAD, and also asthma, are disease of reduced lung function in which antimuscarinic bronchodilators are known to improve airway patency. However, existing agents are non-selective for smooth muscle muscarinic sites in lung and this reduces their effectiveness as bronchodilators and leads to unwanted side effects. Sub-types of muscarinic receptor are now known to exist in the airways (see P. J. Barnes, P. Minette and J. Maclagan, TIPS, 1988, 9, 412.); M1 receptors are present on sympathetic nerves and parasympathetic ganglia; M2 receptors on pulmonary cholinergic nerves (pre-junctional inhibitory receptors) and M3 receptors are located on smooth muscle (post-junctional receptors). The compounds of the present invention generally have bronchospasmolytic effects at doses which do not significantly affect receptors in other tissues such as brain, heart, gastro-intestinal tract, eye and salivary gland. Furthermore, they generally show selectivity for the lung post-junctional M3 receptors as opposed to the pulmonary pre-junctional M2 receptors and cardiac M2 receptors. Therapeutic action at some other smooth muscle sites may be envisaged. For example, the compounds are also likely to be useful in treating urinary incontinence.